Summary/Abstract Malaria remains one of the most important global health challenges, with an estimated 216 million cases and 445,000 deaths each year. Malaria disproportionately affects sub-Saharan Africa, where 90% of cases and deaths occur. Significant progress in malaria control has been realized in the last decade due to increased access to proven interventions, including long lasting insecticidal nets (LLINs), indoor residual spraying of insecticides (IRS), and effective case management with artemisinin-based combination therapies (ACTs). However, progress has not been uniform, and in fact slowest in countries with the highest burden, such as Uganda. Thus, new interventions are urgently needed in Uganda and other high burden African countries. LLINs are the most widely used vector control intervention in Africa, but the spread of pyrethroid resistance has threatened efficacy. New LLINs have been developed that combine the standard pyrethroid insecticide with a synergist, piperonyl butoxide (PBO), which is capable of reversing pyrethroid resistance in some anopheline vectors. However, data on the efficacy of LLINs with PBO from clinical trials with epidemiological outcomes are limited. Researchers in Uganda are currently conducting a cluster-randomized trial to compare LLINs with and without PBO, but only in areas where IRS has not been implemented. In 2020-21, Uganda plans to conduct its next national LLIN distribution campaign, including areas of Uganda where IRS has been implemented. This campaign offers an opportunity to evaluate for the first time the impact of LLINs with PBO in the setting of IRS from a high burden African country using a rigorous cluster-randomized trial design. Our specific aims will be: (1) to establish a malaria surveillance system for estimating the incidence of malaria in catchment areas around health facilities, (2) to compare the impact of IRS plus LLINs with PBO vs. IRS plus LLINs without PBO on the burden of malaria in Uganda, and (3) to compare the costs, cost-effectiveness, and incremental gain costs of IRS plus LLINs with PBO vs. IRS plus LLINs without PBO. The project outlined in this proposal will provide invaluable data on whether new generation LLINs containing PBO provides a cost-effective means of reducing the burden of malaria in areas where IRS has been implemented. In addition, we will help create an efficient and sustainable system for generating accurate estimates of malaria incidence to measure the impact of population level control interventions and, more broadly, to assess for temporal and geographic trends. To ensure that research findings are of direct relevance to ongoing malaria control efforts, the project will be integrated into ongoing activities and conducted in collaboration with the Uganda National Malaria Control Program, international donors and other stakeholders.